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Host Gene Induction and Transcriptional Reprogramming in Kaposi’s Sarcoma-Associated Herpesvirus (KSHV/HHV-8)-Infected Endothelial, Fibroblast, and B Cells

Insights into Modulation Events Early during Infection

¹Department of Microbiology, Molecular Genetics and Immunology, ²Bioinformatics Core, and ³Microarray Core, The University of Kansas Medical Center, Kansas City, Kansas

Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) is etiologically linked to the endothelial tumor Kaposi’s sarcoma and with two lymphoproliferatve disorders, primary effusion lymphoma and multicentric Castleman’s disease. HHV-8 infects a variety of target cells both in vivo and in vitro, binds to the in vitro target cells via cell surface heparan sulfate, and uses the ₃ß₁ integrin as one of the entry receptors. Within minutes of infection, HHV-8 induced the integrin-mediated signaling pathways and morphological changes in the target cells (S. M. Akula et al., Cell, 108: 407–419, 2002; P. P. Naranatt et al., J. Virol., 77: 1524–1539, 2003). As an initial step toward understanding the role of host genes in HHV-8 infection and pathogenesis, modulation of host cell gene expression immediately after infection was examined. To reflect HHV-8’s broad cellular tropism, mRNAs collected at 2 and 4 h after infection of primary human endothelial [human adult dermal microvascular endothelial cells (HMVECd)] and foreskin fibroblast [human foreskin fibroblast (HFF)] cells and human B cell line (BJAB) were analyzed by oligonucleotide array with 22,000 human transcripts. With a criteria of >2-fold gene induction as significant, 1.72% of the genes were differentially expressed, of which, 154 genes were shared by at least two cells and 33 genes shared by all three cells. HHV-8-induced transcriptional profiles in the endothelial and fibroblast cells were closely similar, with substantial differences in the B cells. In contrast to the antiapoptotic regulators induced in HMVECd and HFF cells, proapoptotic regulators were induced in the B cells. A robust increase in the expression of IFN-induced genes suggestive of innate immune response induction was observed in HMVECd and HFF cells, whereas there was a total lack of immunity related protein inductions in B cells. These striking cell type-specific behaviors suggest that HHV-8-induced host cell gene modulation events in B cells may be different compared with the adherent endothelial and fibroblast target cells. Functional clustering of modulated genes identified several host molecules hitherto unknown to HHV-8 infection. These results indicate that early during infection, HHV-8 reprograms the host transcriptional machinery regulating a variety of cellular processes including apoptosis, transcription, cell cycle regulation, signaling, inflammatory response, and angiogenesis, all of which may play important roles in the biology and pathogenesis of HHV-8.

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